Globally, more than 11% of babies are born before 37 weeks of gestation (premature), and the number of premature births is increasing worldwide (Blencowe et al., (2012) Lancet 379:2162-2172). Bronchopulmonary dysplasia (BPD) is the major pulmonary morbidity of extreme prematurity, with an estimated 14,000 new diagnoses made each year in the United States (Van Marter (2009) Semin Fetal Neonatal Med 14:358-366) and annual care costs upwards of $26 billion (Cole et al., (2011) Pediatrics 127:363-369). Equally important is the concept that prematurity and BPD may be a chronic respiratory condition. After their initial care, half of premature patients will be rehospitalized for respiratory causes in early childhood (Furman et al., (1996) The Journal of Pediatrics 128:447-452). Follow up studies of children and young adults born prematurely show evidence of impaired pulmonary function, manifesting signs of obstructive pulmonary disease with decreased predicted forced expiratory volume in 1 second (FEV1) (Fawke et al. (2010) Am J Respir Crit Care Med 182:237-247), decreased predicted forced expiratory flow (FEF25-75%) (Vollsaeter et al. (2013) Thorax 68:767-776), and reduced exercise capacity (Vrijlandt et al., (2006) Am J Respir Crit Care Med 173:890-896). Indeed, increased airway reactivity and asthma-like symptoms are common long-term pulmonary consequences of both premature birth and BPD (Baraldi et al., (2009) Early Human Development 85:S1-3).
S-nitrosothiols (SNOs) are ubiquitous protein molecules in which nitric oxide is bound to a cysteine thiol, which regulate the biologic activity of many target proteins (Foster et al., (2009) Trends in Molecular Medicine 15:391-404). One such SNO is S-nitrosoglutathione (GSNO), an endogenous bronchodilator, which exhibits 100-fold more potency than the asthma medication theophylline (Gaston et al., (1994) J Pharmacol Exp Ther 268:978-984). GSNO is a critical modulator of airway reactivity in asthmatic animal models (Blonder et al., (2014) BMC Pulm Med 14:3). Airway levels of GSNO are dramatically decreased in pediatric cases of severe asthmatic respiratory failure (Gaston et al., (1998) Lancet 351:1317-1319) and GSNO reductase (GSNOR, also known as alcohol dehydrogenase 5, adh5), the enzyme responsible for the catabolic breakdown of GSNO, is elevated in asthma patients that display increased airway reactivity (Que et al. (2009) American Journal of Respiratory and Critical Care Medicine 180:226-231).
Traditional asthma therapies are not always effective in this patient population. Interestingly, the asthma phenotype in premature infants differs from the allergic asthma seen in their term-born peers (Filippone et al., (2013) Eur Respir J 42:1430-1431). The increased risk for airway reactivity in surviving premature neonates is strongly associated with a history of prolonged supplemental oxygen exposure and bronchopulmonary dysplasia (BPD), compared to the reactivity observed in full term peers, which instead is associated with a history of genetic inheritance, allergy, airway inflammation, and cigarette exposures (Halvorsen et al., (2005) Pediatr Allergy Immunol 16:487-494). Yet, former premature infants are twice as likely to be prescribed asthma medications compared to their full term school-age classmates (Hack et al., (2005) JAMA 294:318-325) and premature infants, with or without BPD, continue to be at very high risk for airway reactivity in infancy and childhood (Fawke et al. (2010) Am J Respir Crit Care Med 182:237-247; Been et al., (2014) PLoS Med 11:e1001596; Hennessy et al., (2013) J Pediatr 163:61-66 e61). Thus, novel therapies are needed in this growing patient population.